Structural Differences between Tumor and Normal Microvasculature

Normal microvasculature is hierarchically organized. The capillary network branches from arterioles with continuous or metarterioles with discontinuous layers of smooth muscle cells. In both cases precapillary sphincters may regulate blood flow. Blood flow regulation is also facilitated by arteriovenous anastomoses. The capillaries are usually made up by a continuous layer of endothelial cells that are joined together by tight junctions. In some organs, such as in parts of the gut and in endocrine glands, fenestrated endothelium prevails. Pericytes originating from mesenchymal cells and a basement membrane regularly embrace continuous endothelium-type capillaries, whereas pericytes are rarely found in fenestrated capillaries. Gaps between endothelial cells are seen only in discontinuous, sinusoidal vessels in the spleen, liver, and bone marrow. In these vessels basement membranes are missing.

Tumor microvasculature is characterized by a lack of hierarchy and differentiation. Even large caliber vessels are mainly composed of no more components than an endothelium and a basement membrane (Figure 1). Because of the usually higher interstitial pressure the endothelium may decrease in height and appear flattened. Only sprout formations and early vessel forms, such as in the tumor invasion front, reveal an organelle-rich and comparatively high endothelium (Figure 1b,c). Villus-like protrusions of the luminal surfaces indicate the young age of these vessels. Abluminal protrusions of cell ramifications, again, indicate active migration and new sprouting. The thinning of the endothelium sets in with further stabilization and increase in the luminal diameter. However, only a part of the early forms persists: Many early forms undergo degeneration and destruction just like those sprouts that did not fuse with others. Until now no reliable morphometric data have been available on the fate of sprouts and early forms. We have the impression that at least two thirds of all formed sprouts will not differentiate into early forms or established vessels.

Fenestrations shut by diaphragms are rarely seen (Figure 1d), whereas discontinuities or gaps that allow for hemorrhage and facilitate permeability are common features irrespective of the origin of the tumor (Figure 1e). Cell contacts are usually poorly differentiated, and no complex contact structures exist even in well-established vessels and late forms. Pericytes are frequently missing.

Comparisons of the structural features of different human sarcomas, melanomas, and carcinomas xenografted onto nude mice as well as a variety of human primary tumors (colorectal, renal, and larynx carcinomas) did not show tumor cell line or tumor entity specific cell structure pattern. This might well have consequences for targeting approaches. In general, the number of intracytoplasmic contractile filaments is reduced, which contradicts any possible blood flow regulation by pericyte or endothelial cell contractility. Blood flow is regulated primarily on the level of preexisting arteries and arterioles nourishing the tumor, resulting in heterogeneous blood flow. Apart from incorporated vessels no clearly demarcated arterial sphincters are visible within the newly formed tumor vascular network. Autonomous nerves are also detectable only in the tumor periphery as incorporated nerve fibers. Thus, low structural stability is accompanied by lacking regulation.

The difficulties frequently seen when using panendothe-lial cell markers such as anti-CD31 or anti-FVIII for labeling tumor microvessels indicate a functional and structural heterogeneity of lumen-confining cells in tumors. This is at least in part due to the participation of nonendothelial cells in the vessel wall formation. Newly formed vessels composed of cells with extremely different cell organelle contents indicate the involvement of different cell types (Figure 1d). Sometimes "endothelial cells" could be observed that engulfed bundles of collagen fibers.

It has been well known for 30 years that pericytes may be formed not only by the angioblastic pathway, but also from mesenchymal cells. Likewise, since then evidence has accumulated that tumor cells themselves may be involved in vessel wall building. Interstitial plasma flow may take place in channels completely lined by nonendothelial cells (Figure 1f), for which the term vascular mimicry was recently coined.

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